Depression and anxiety in caregivers of patients with functional seizures.

OBJECTIVE: Contrary to patients, the psychological impact of functional seizures to caregivers has not been adequately investigated. This study aimed to evaluate the rates and determinants of depression and anxiety in caregivers of patients with functional seizures. METHODS: Patients with functional seizures and their caregivers completed surveys about demographic, disease-related, and psychosocial characteristics. Rates and determinants of depression and anxiety were evaluated using the Beck Depression and Anxiety Inventory scores as dependent variables and patient and caregiver characteristics as independent variables. RESULTS: Twenty-nine patients (76% female, mean age of 37 years) and their caregivers (59% female, mean age of 43 years) were recruited. Symptoms of anxiety and/or depression were present in 96% of patients (96% depression, 92% anxiety) and 59% of caregivers (52% depression, 50% anxiety). Specifically, 31% of caregivers manifested mild depression, 14% moderate depression, and 7% severe depression, whereas 48% were not depressed. Similarly, 14% of caregivers manifested mild anxiety, 29% moderate anxiety, and 7% severe anxiety, whereas 50% were not anxious. Patient and caregiver depression levels strongly correlated (r = .73, p < .0001). The presence of anxiety and depression in the caregiver was associated with male patient gender (p = .02), patient depression level (p = .002), the caregiver being a parent or sibling (p = .02), and caregiver burden (p = .0009). SIGNIFICANCE: Caregivers of patients with functional seizures experience high rates of anxiety and depression, explained by specific demographic and psychosocial factors that could act as intervention targets.

PRES and RCVS: Two Distinct Entities or a Spectrum of the Same Disease?

OBJECTIVES: To report a case of a patient with overlapping posterior reversible encephalopathy syndrome (PRES) and reversible cerebral vasoconstriction syndrome (RCVS), and review the existing literature emphasizing the pathophysiological overlap of these two entities. MATERIALS AND METHODS: We conducted a literature search in electronic database PubMed identifying studies reporting the overlap of PRES and RCVS. RESULTS: PRES and RCVS are two increasingly recognized entities that share similar clinical and imaging features. PRES is characterized by vasogenic edema predominantly in the parieto-occipital regions, associated with acute onset of neurological symptoms including encephalopathy, seizures, headaches, and visual disturbances. RCVS is characterized by reversible segmental and multifocal vasoconstriction of the cerebral arteries and classically presents with thunderclap headache, with or without associated focal neurological deficits and seizures. PRES is frequently associated with uncontrolled hypertension but can also be seen in the setting of renal failure, exposure to cytotoxic agents, or pre-eclampsia. RCVS is often triggered by exposure to vasoactive agents, postpartum state, or immunosuppression. We report a case of a patient presenting with vision changes and hemiparesis, and found to have extensive cytotoxic and vasogenic edema involving the cortex and subcortical white matter on brain imaging. These changes were primarily noted in the parieto-occipital and brainstem regions, along with features of reversible vasculopathy on vascular imaging suggestive of coexisting PRES and RCVS. CONCLUSIONS: PRES and RCVS share precipitating factors, clinical and radiological features, and frequently co-exist, suggesting a common pathophysiological mechanism related to reversible dysregulation of cerebral vasculature, endothelial dysfunction, and breakdown of the blood-brain barrier.

Clinical Reasoning: A 55-Year-Old Woman With Recurrent Episodes of Aphasia and Vision Changes.

A 55-year-old woman presented with recurrent episodes of headache, vision changes, and language disturbances. Brain MRI showed multifocal white matter lesions, microhemorrhages, and enlarged perivascular spaces. After an extensive and unrevealing workup, she underwent a biopsy of brain and meninges that revealed thick and hyalinized leptomeningeal and cortical vessel walls that were strongly positive for ß-amyloid by immunohistochemical staining, suggestive of cerebral amyloid angiopathy (CAA). CAA can present as a spectrum of inflammatory responses to the deposition of amyloid-ß in the vessel walls. Her clinical presentation, radiologic, and histopathologic findings supported a diagnosis of probable CAA-related inflammation (CAA-ri). Although an uncommon entity, it is important to recognize it because most patients respond to immunosuppressive therapy.

Translating Phenomenology of Psychogenic Nonepileptic Seizures Into Nosology: Insights From Patients' and Caregivers' Profiles.

BACKGROUND: Patients with psychogenic nonepileptic seizures (PNES) can be semiologically dichotomized into those with hyperkinetic and those with paucikinetic events. The objective of this study was to compare characteristics of patients with diverse phenomenology and their caregivers to evaluate for differences that could inform about disease nosology. METHODS: Patients and caregivers monitored at the Epilepsy Monitoring Unit completed surveys about sociodemographic and disease characteristics, treatment and health care utilization, physical and psychosocial impact, and epilepsy knowledge. Patients were classified into hyperkinetic versus paucikinetic based on their recorded events. Comparison of the 2 populations was performed using Student t test for continuous variables and Fischer exact test for categorical variables. RESULTS: Forty-three patients with Epilepsy Monitoring Unit confirmed PNES and 28 caregivers were enrolled. Patients with hyperkinetic events were more commonly non-White patients and necessitated greater caregiving time. Otherwise, no statistically significant differences were seen between the 2 semiologically diverse groups of patients and caregivers in their sociodemographic (age, sex, employment, income, marital, and education) and disease (age of onset, duration, seizures frequency) characteristics, treatment (number of antiseizure medications before diagnosis, side effects) and health care utilization (emergency room visits, hospitalizations, clinic visits), physical (injuries) and psychosocial (depression, anxiety, quality of life, stigma, burden) characteristics, nor in their knowledge about seizures. CONCLUSIONS: Hyperkinetic events were more frequently encountered in non-White patients and required more caregiving time. Further research is required to elucidate if phenomenological dichotomy of PNES can inform about their nosological basis, and if it can guide treatment and define prognosis.

Depression and Anxiety in Adult Persons With Epilepsy and Their Caregivers: A Survey-Based Study at a Tertiary Care Center.

ABSTRACT: This study evaluated the rates of depression and anxiety and their determinants in adult persons with epilepsy and their caregivers. Both completed surveys about demographic, disease-related, and psychosocial characteristics. One hundred patients and caregivers participated. A mood disorder was present in 89% of patients and 56% of caregivers. In the univariate analysis, the presence of mood disorder in the patient was associated with being unmarried, unemployed, frequent hospitalizations, side effects from polypharmacy, patient stigma, patient quality of life, caregiver anxiety, and caregiver burden. In the multivariate analysis, medication side effects sustained as an important determinant. In the univariate analysis, the presence of mood disorder in the caregiver was associated with seizure frequency, patient anxiety, patient quality of life, caregiver stigma, and caregiver burden. In the multivariate analysis, patient anxiety level and caregiver burden sustained as important determinants. Adult persons with epilepsy and their caregivers experience high rates of mood disorders, explained by certain clinical factors.

DDESVSFS: A simple, rapid and comprehensive screening tool for the Differential Diagnosis of Epileptic Seizures VS Functional Seizures.

OBJECTIVE: Functional seizures (FS) are often misclassified as epileptic seizures (ES). This study aimed to create an easy to use but comprehensive screening tool to guide further evaluation of patients presenting with this diagnostic dilemma. MATERIALS AND METHODS: Demographic, clinical and diagnostic data were collected on patients admitted for video-EEG monitoring for clarification of their diagnosis. Upon discharge, patients were classified as having ES vs FS. Using the collected characteristics and video-EEG diagnosis, we created a multivariable logistic regression model to identify predictors of ES. Then, we trained an integer-coefficient model with the most frequently selected predictors, creating a pointing system coined DDESVSFS, with scores ranging from -17 to +8 points. RESULTS: 43 patients with FS and 165 patients with ES were recruited. In the final integer-coefficient model, 8 predictors were identified as significant in differentiating ES from FS: normal electroencephalogram (-3 points), predisposing factors for FS (-3 points), increased number of comorbidities (-3 points), semiology suggestive of FS (-4 points), increased seizure frequency (-4 points), longer disease duration (+3 points), antiepileptic polypharmacy (+2 points) and compliance with antiepileptic drugs (+3 points). Cumulative scores of ≤ -9 points carried <5% predictive value for ES, while cumulative scores of ≥ -1 points carried >95% predictive value. The model performed well (AUC: 0.923, sensitivity: 0.945, specificity: 0.698). CONCLUSIONS: We propose DDESVSFS as a simple, rapid and comprehensive prediction score for the Differential Diagnosis of Epileptic Seizures VS Functional Seizures. Large prospective studies are needed to evaluate its utility in clinical practice.

Mind the gap: health disparities in families living with epilepsy are significant and linked to socioeconomic status.

There is limited information on disparities of people with epilepsy (PWE) and, foremost, their caregivers. The objective of this study was to comprehensively compare between PWE and caregivers with low socioeconomic status (SES) and those with high SES for disparities in demographic and epilepsy characteristics, treatment and health care utilization, physical and psychosocial impact, and knowledge about epilepsy. PWE and caregivers completed surveys about the aforementioned outcomes during their epilepsy clinic visit or epilepsy monitoring unit admission. Associations were evaluated using SES as a binary independent variable and the patient and caregiver related outcomes as dependent variables. Thirty-eight patients with low SES and 88 patients with high SES were recruited. Patients with low SES were more commonly non-white, uninsured, unemployed, of lower educational attainment and living in larger households. They were more likely to visit the emergency room for their seizures, were more frequently on polypharmacy and experienced more AED adverse effects. They exhibited higher depression and anxiety levels and worse quality of life. Twenty-two caregivers with low SES and 66 caregivers of high SAS were recruited. Caregivers with low SES were more likely to be non-white and single. They manifested poorer knowledge about epilepsy. There are notable inequalities in demographic, treatment-related and health care utilization aspects of care of PWE, as well as in the psychosocial impact of their disease. Additional demographic and epilepsy knowledge-related disparities are recognized in caregivers of PWE. Identification of those disparities is a critical step in the creation of appropriate interventions to eliminate them.

Caregiver burden in psychogenic non-epileptic seizures.

OBJECTIVE: Caregiver burden in psychogenic non-epileptic seizures (PNES) is an important but understudied reality. The objective of this exploratory study was to quantify caregiver burden in PNES and to identify the patient and caregiver characteristics associated with it. METHODS: PNES patients and their identified caregivers completed surveys about demographic, disease related and psychosocial characteristics during their Epilepsy Monitoring Unit (EMU) admission. Associations were evaluated using the Zarit Caregiver Burden Inventory (ZCBI) score as an independent variable and the patient and caregiver related characteristics as dependent variables. RESULTS: 43 patients and 28 caregivers were recruited. The patients were on average 36 years old, single women, unemployed, with some college education. They suffered from PNES on average for 8 years, having approximately 20 seizures per month, and were previously maintained on ≥ 2 antiseizure medications. Most caregivers were first degree relatives with a mean age of 43 years, married employed women of higher educational attainment, typically cohabitating with the patients. Caregiver burden was within the mild-moderate range (ZCBI mean score 28). The burden appeared higher in caregivers of male patients. Patient quality of life, depression and medication side effects were associated with that burden. Additionally, caregiver stigma, depression and anxiety emerged as potential contributors. In the multivariate analysis, patient quality of life and caregiver depression stood out as the most robust factors. CONCLUSION: There is substantial caregiver burden in PNES. It is associated with both the patient and the caregiver psychosocial well-being in a reciprocal relationship.

Stigma in psychogenic nonepileptic seizures.

OBJECTIVE: There is scarce literature on stigma in families living with psychogenic nonepileptic seizures (PNES). Using a cohort of patients with epileptic seizures (ES) and their caregivers as controls, we aimed to quantify the level of patient and caregiver stigma in PNES and identify associations of patient and caregiver characteristics with it. METHODS: Patients with PNES and ES and their caregivers completed surveys about demographic, clinical, and psychosocial characteristics. Multivariate regression analysis was used to identify correlates of patient and caregiver stigma. RESULTS: Forty-three patients with PNES and 165 patients with ES were recruited. Compared with patients with ES, patients with PNES had shorter disease duration, higher seizure frequency, normal diagnostic data, poorer psychosocial health, and fewer antiseizure medications (ASMs). A total of 76.5% of patients with PNES and 59.5% of patients with ES felt stigmatized. Patient stigma level was higher in patients with PNES compared with those with ES, and it was negatively associated with patient quality of life (QOL). Additionally, 28 caregivers of patients with PNES and 99 caregivers of patients with ES were recruited. There were no significant demographic, caregiving, or psychosocial differences between the two caregiver cohorts. Seventy-two percent of caregivers of patients with PNES and 47% of caregivers of patients with ES felt stigmatized. Caregiver stigma level was also higher in caregivers of patients with PNES compared with caregivers of patients with ES, and it was negatively associated with patient QOL and positively associated with patient and caregiver anxiety. CONCLUSION: Compared with those with ES, patients and caregivers living with PNES experience stigma more frequently and to a higher extent. Patient QOL emerges as a consistent correlate of that stigma.

Socioeconomic disparities in patients with psychogenic nonepileptic seizures and their caregivers.

OBJECTIVE: There is no information on disparities of patients with psychogenic nonepileptic seizures (PNES) and their caregivers. The objective of this exploratory study is to compare patients with PNES and caregivers with low socioeconomic status (SES) with those of high SES for disparities in healthcare use, seizures, medication adverse effects, psychosocial impact, and knowledge about epilepsy. METHODS: Patients with PNES and caregivers completed surveys about the aforementioned outcomes during their Epilepsy Monitoring Unit (EMU) admission. Associations were evaluated using SES as a binary independent variable and the patient- and caregiver-related outcomes as dependent variables. RESULTS: Forty-three patients and 28 caregivers were recruited. The majority of patients were on average 36 years old, single women, unemployed, with some college education. The majority had PNES for 8 years averaging 20 seizures per month and were maintained on ≥2 antiepileptic drugs (AEDs) prior to their EMU admission. Most caregivers were first-degree relatives with a mean age of 43 years, married employed women of higher educational attainment, typically cohabitating with the patients. Low SES patients showed poorer knowledge about epilepsy (p < 0.0001) and higher anxiety levels (p = 0.03). Conversely, high SES patients demonstrated poorer social functioning (p = 0.04). High SES caregivers showed higher caregiving burden (p = 0.01). CONCLUSION: There are noteworthy disparities in patients with PNES of different SES and their caregivers. Identification of those disparities is a critical step in the creation of appropriate interventions to address them.

Reduced noradrenergic innervation of ventral midbrain dopaminergic cell groups and the subthalamic nucleus in MPTP-treated parkinsonian monkeys.

There is anatomical and functional evidence that ventral midbrain dopaminergic (DA) cell groups and the subthalamic nucleus (STN) receive noradrenergic innervation in rodents, but much less is known about these interactions in primates. Degeneration of NE neurons in the locus coeruleus (LC) and related brainstem NE cell groups is a well-established pathological feature of Parkinson's disease (PD), but the development of such pathology in animal models of PD has been inconsistent across species and laboratories. We recently demonstrated 30-40% neuronal loss in the LC, A5 and A6 NE cell groups of rhesus monkeys rendered parkinsonian by chronic administration of 1-methyl-4-phenyl-1,2,3,6-tetrahydropyridine (MPTP). In this study, we used dopamine-beta-hydroxylase (DßH) immunocytochemistry to assess the impact of this neuronal loss on the number of NE terminal-like varicosities in the substantia nigra pars compacta (SNC), ventral tegmental area (VTA), retrorubral field (RRF) and STN of MPTP-treated parkinsonian monkeys. Our findings reveal that the NE innervation of the ventral midbrain and STN of normal monkeys is heterogeneously distributed being far more extensive in the VTA, RRF and dorsal tier of the SNC than in the ventral SNC and STN. In parkinsonian monkeys, all regions underwent a significant (~50-70%) decrease in NE innervation. At the electron microscopic level, some DßH-positive terminals formed asymmetric axo-dendritic synapses in VTA and STN. These findings demonstrate that the VTA, RRF and SNCd are the main ventral midbrain targets of ascending NE inputs, and that these connections undergo a major break-down in chronically MPTP-treated parkinsonian monkeys. This severe degeneration of the ascending NE system may contribute to the pathophysiology of ventral midbrain and STN neurons in PD.

Critical role of arginine 160 of the EutB protein subunit for active site structure and radical catalysis in coenzyme B12-dependent ethanolamine ammonia-lyase.

The protein chemical, kinetic, and electron paramagnetic resonance (EPR) and electron spin-echo envelope modulation (ESEEM) spectroscopic properties of ethanolamine ammonia-lyase (EAL) from Salmonella typhimurium with site-directed mutations in a conserved arginine residue (R160) of the active site containing EutB protein subunit have been characterized. R160 was predicted by a comparative model of EutB to play a critical role in protein structure and catalysis [Sun, L., and Warncke, K. (2006) Proteins: Struct., Funct., Bioinf. 64, 308-319]. R160I and R160E mutants fail to assemble into an EAL oligomer that can be isolated by the standard enzyme purification procedure. The R160K and R160A mutants assemble, but R160A EAL is catalytically inactive and reacts with substrates to form magnetically isolated Co(II) and unidentified radical species. R160A EAL activity is resurrected by externally added guanidinium to 2.3% of wild-type EAL. R160K EAL displays catalytic turnover of aminoethanol, with a 180-fold lower value of k(cat)/ K(M) relative to wild-type enzyme. R160K EAL also forms Co(II)-substrate radical pair intermediate states during turnover on aminoethanol and (S)-2-aminopropanol substrates. Simulations of the X-band EPR spectra show that the Co(II)-substrate radical pair separation distances are increased by 2.1 +/- 1.0 A in R160K EAL relative to wild-type EAL, which corresponds to the predicted 1.6 A change in arginine versus lysine side chain length. 14N ESEEM from a hyperfine-coupled protein nitrogen in wild type is absent in R160K EAL, which indicates that a guanidinium 14N of R160 interacts directly with the substrate radical through a hydrogen bond. ESEEM of the 2H-labeled substrate radical states in wild-type and R160K EAL shows that the native separation distances among the substrate C1 and C2, and coenzyme C5' reactant centers, are conserved in the mutant protein. The EPR and ESEEM measurements evince a protein-mediated force on the C5'-methyl center that is directed toward the reacting substrate species during the hydrogen atom transfer and radical rearrangement reactions. The results indicate that the positive charge at the residue 160 side chain terminus is required for proper folding of EutB, assembly of a stable EAL oligomer, and catalysis in the assembled oligomer.

Comparative peptide binding studies of the PABC domains from the ubiquitin-protein isopeptide ligase HYD and poly(A)-binding protein. Implications for HYD function.

The PABC domain is a peptide-binding domain that is specifically found in poly(A)-binding protein (PABP) and a HECT ubiquitin-protein isopeptide ligase (E3) known as HYD (hyperplastic discs), EDD (E3 isolated by differential display), or Rat100. The PABC domain of PABP recruits various regulatory proteins and translation factors to poly(A) mRNAs through binding of a conserved 12-amino acid peptide motif, PAM2 (PABP-interacting motif 2). In contrast, little is known about the specificity or function of the domain from HYD. Here, we used isothermal calorimetry and surface plasmon resonance titrations to show that the PABC domain of HYD binds PAM2 peptides with micromolar affinity. NMR chemical shift perturbations were used to map the peptide-binding site in the PABC domain of HYD. The structural features of binding are very similar to those of the interactions with the domain of PABP, which explains the overlapping peptide specificity and binding affinity. We identified the anti-proliferative Tob proteins as potential binding partners of HYD. This was confirmed by glutathione S-transferase pulldown and immunoprecipitation experiments demonstrating the interaction with full-length Tob2. Altogether, our results point to a role of the PABC domain as a protein-protein interaction domain that brings together the processes of translation, ubiquitin-mediated protein degradation, and cell cycle control.